|Year : 2007 | Volume
| Issue : 4 | Page : 259-262
Niemann-Pick disease Type C - Sea-blue histiocytosis: Phenotypic and imaging observations and mini review
KS Praveen1, S Sinha1, TC Yasha2, UB Muthane1, S Ravishankar3, S Sangeetha2, KT Shetty4, AB Taly1
1 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
2 Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
3 Department of Neuroradiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
4 Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore - 560 029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
We present a report on an 18-year-old boy with Niemann-Pick disease Type C (NP-C) who presented with progressive decline in scholastic performance since 9 years of age. At 12 years, he developed abnormal behavior and after 2 years had insidious onset, progressive gait ataxia and dysarthria followed by dystonia of the right upper extremity, excessive drooling, dysphagia and nasal regurgitation. He had coarse facies, depressed nasal bridge, high arched palate, crowded teeth, splenomegaly and peculiar facial grin. In addition, impaired vertical saccadic and pursuit eye movements, brisk muscle stretch reflexes and limb and gait ataxia were observed. He had a low IQ of 47 on Binet-Kamat test. The ultrasound examination of the abdomen confirmed the presence of moderate splenomegaly. Magnetic resonance imaging brain showed symmetrical leucoencephalopathy and mild cerebellar atrophy. Bone marrow aspiration showed numerous foamy macrophages and sea-blue histiocytes suggesting the diagnosis of NP-C.
Keywords: Magnetic resonance imaging, Niemann-Pick disease Type-C, sea-blue histiocytes
|How to cite this article:|
Praveen K S, Sinha S, Yasha T C, Muthane U B, Ravishankar S, Sangeetha S, Shetty K T, Taly A B. Niemann-Pick disease Type C - Sea-blue histiocytosis: Phenotypic and imaging observations and mini review. Ann Indian Acad Neurol 2007;10:259-62
|How to cite this URL:|
Praveen K S, Sinha S, Yasha T C, Muthane U B, Ravishankar S, Sangeetha S, Shetty K T, Taly A B. Niemann-Pick disease Type C - Sea-blue histiocytosis: Phenotypic and imaging observations and mini review. Ann Indian Acad Neurol [serial online] 2007 [cited 2019 Jun 20];10:259-62. Available from: http://www.annalsofian.org/text.asp?2007/10/4/259/37820
| Introduction|| |
Niemann-Pick disease Type C (NP-C) is an autosomal recessive neurovisceral lipidosis with protean manifestations, which include: splenomegaly (91%), hepatomegaly (52%), cognitive decline and poor scholastic performance (78%), ataxia (70%), pyramidal signs (48%), seizure (39%), dysarthria (39%), involuntary movements and hypotonia (22%) and dystonia (22%) in majority of the cases.  Neurological manifestations commonly occur between 5 and 9 years (57%) and less commonly between 9 and 13 years (22%). Visceral organs and bone marrow are variably infiltrated with foamy macrophages and sea-blue histiocytes (SBH) in most instances. 
In this report, we describe the phenotype, bone marrow and MRI findings of a patient of Niemann-Pick disease Type C and discuss this in the light of recent knowledge.
| Case Report|| |
An 18-year-old boy, elder of two siblings, born of second-degree consanguineous parentage had an unremarkable perinatal history and normal developmental milestones. His mother reported progressive decline in scholastic performance from 9 years of age. There was no family history of neurological illness. At 12 years, he developed visual hallucinations, delusions of reference and ideas of persecution, hyper-religiosity, talking to self and unprovoked crying episodes. He received risperidone (2 mg/day) and his behavior improved over the next 4 years and the medications could be stopped for last 1½ year. For the last 5 years, he had developed insidious onset, progressive gait ataxia and dysarthria. Subsequently, dystonia of right upper extremity was evident while walking for the past 1 year. Excessive drooling, dysphagia and nasal regurgitation were observed for a month prior to presentation. Till a year ago, he was attending a special school for mentally handicapped children.
His height (150 cm), weight (43 kg) and head circumference (54 cm) were normal for age. He had coarse facies, depressed nasal bridge, high arched palate and crowded teeth. Firm and nontender splenomegaly was observed (3 cm below the costal margin). He had a peculiar facial grin and his speech was slow and dysarthric. Both saccadic and pursuit eye movements in vertical directions were impaired, while the horizontal movements were normal. Optokinetic nystagmus was also impaired in vertical plane. However, the eye movements were normal with oculocephalic reflex maneuver. Dystonia of both upper extremities (R > L) was noted, which increased with rapid alternating movements and walking. The muscle stretch reflexes were brisk and plantar response was flexor. He had bilateral finger-nose and knee-heel ataxia. His gait was wide-based, ataxic with decreased arm swing (R > L). He had a low IQ of 47 on Binet-Kamat test.
Routine hemogram, including hemoglobin, leucocyte counts, ESR and peripheral smear, were normal. Blood biochemical tests such as glucose, renal and liver function tests, lipid profile and other metabolic screening and electrolytes were normal. Routine urinary examination was normal and analysis for amino acids, reducing substances and mucopolysaccharides were not positive. Thyroid function tests were normal. Serum arylsulfatase A and B and hexosaminidase A and B levels were within normal range. Sphingomyelinase activity of WBCs was within the normal limits (15.4 nmol/mg protein/h). Slit lamp examination did not reveal Kayser-Fleischer (KF) corneal ring. Skull and chest X-rays were normal. Electrophysiological evaluation with scalp electroencephalography, nerve conduction studies, visual evoked potential, brain stem evoked potential and somatosensory evoked potential studies were within the normal limits. The ultrasound examination of the abdomen revealed moderate splenomegaly. MRI brain showed symmetrical bilateral periventricular and deep white matter hyperintensity on fluid-attenuated inversion recovery (FLAIR) sequence and T2W images, which were isointense on T1WI. MR spectroscopy was normal. Cerebellar foliae in the hemispheres and vermis were prominent suggesting cerebellar atrophy [Figure - 1]A and B. Bone marrow aspiration showed numerous SBH containing several large, coarse sea-blue granules within the cytoplasm. There were also many pale, foam cells with bloated, multivacuolated cytoplasm. Transition cells were also observed [Figure - 2]A, B and C.
| Discussion|| |
The initial manifestation in our patient was learning difficulty and behavioral disturbances which was later followed by motor symptoms. Many otherwise well-functioning children with this disease have a long history of learning disorders and impaired school performances prior to the development of other symptoms. Static learning impairment and progressive dementia are frequent in NP-C.  Psychosis, behavioral disturbances, overt hallucinations and delusions may occasionally be the early features.  Phenotypic features such as gait ataxia, dysarthria, supranuclear paralysis of vertical gaze, dystonia and splenomegaly observed in our patient; all these features have been documented in the literature. , Facial dystonia, which is an important clue for the diagnosis of GM1 gangliosidosis,  has been reported in "Niemann-Pick C mimics" in our center.  However, prominent facial dystonia was absent in this patient. Pyramidal and extrapyramidal symptoms are common in NP-C.  Dystonia and choreoathetosis may be variable and occur either earlier or later in the course of this disease.  Tremor and bradykinesia are less common and may be superimposed on ataxia and spasticity. Ataxia is frequently an early complaint and profound gait ataxia is common only when the disease progresses.  Spastic and spastic-ataxic dysarthria add to morbidity. Seizures are not uncommon and multiple seizures may be difficult to control at times. 
Vertical supranuclear gaze palsy is a characteristic feature of NP-C; however, it may not be evident early in the course of the disease.  The sequences of oculomotor abnormalities are: (a) loss of vertical (down gaze more than up gaze) volitional saccades with the absence of fast phase of optokinetic nystagmus in the vertical plane, (b) impaired vertical following initially at high velocities, (c) impaired horizontal movements with reduced velocity of saccades to voluntary and optokinetic stimuli and (d) defect of convergence.  The precise site for downgaze paresis is unknown, although the ventrolateral mesencephalic reticular formations have been implicated.  Supranuclear ophthalmoplegia is reported in the following: GM2 gangliosidosis. mitochondrial diseases, glycine encephalopathy, MSUD, Parkinson's disease, Huntington's disease, ataxia telangiectasia, kernicterus, Sylvian aqueduct syndrome, progressive supranuclear palsy, corticobasal degeneration, Whipple's disease, Huntington's chorea, neuroacanthocytosis and Wilson's disease.  These conditions can be differentiated from Niemann-Pick's disease by their characteristic clinical profile and absence of characteristic foam cells in the bone marrow.
CT and MRI of brain may be normal or reveal diffuse atrophy, particularly cerebellar vermian atrophy. The reasons could be the following: (a) the highest levels of NPC 1 gene expressed in neurons in pons and cerebellum and (b) cell-autonomous death of cerebellar purkinje cells.  Cerebellar sections on microscopy show a preferential involvement of Type 2 Golgi cells and atrophy of the inner granular layer.  MR spectroscopy may show a significantly decreased ratio of NAA and creatine  along with phosphocreatine in frontal and parietal cortices, centrum semiovale and caudate.  This might serve as an objective tool to neurologically evaluate these patients at different stages of the disease. Changes are observed in the periventricular white matter in some cases.  Our patient had vermian atrophy and symmetrical leucoencephalopathy.
Histological features of NP-C include numerous reports of foamy cells and/or SBH in the bone marrow aspirates.  Mere presence of the foam cells and SBH has lesser sensitivity and specificity for the diagnosis of NP-C. However, in the appropriate clinical context, their presence leaves little doubt to the diagnosis. Other causes of hereditary lipidoses with SBH are as follows: Niemann-Pick disease Type B  and the exceptional causes are Tay-Sach's, Gaucher's and Wolman's diseases. Reported hematologic and metabolic disorders associated with SBH include the following: alcoholism and hypercholesterolemia, hepatic porphyria, hyperlipidemia, lecithin cholesterol acyltransferase deficiency, idiopathic thrombocytopenic purpura, polycythemia vera, thalassemia, sickle cell anemia, chronic myelogenous leukemia, erythemic myelosis, mycosis fungoides, multiple myeloma, Hodgkin's disease, infectious mononucleosis, Batten's disease, neuroaxonal dystrophy, Takayasu's arteritis.  The sea-blue granules contain phospholipids, glycosphingolipids and ceroids.  Electron microscopy shows characteristic features with foamy cells containing numerous cytolysosomes and SBH having smaller electron dense lysosomes were encountered less frequently. 
The clinical signs of NP-C are caused by abnormal intracellular cholesterol homeostasis.  The knowledge of primary, consistent disturbance in cholesterol deposition has led to development of diagnostic tests, identification of heterozygotes and prenatal detection of this disorder. The most consistent discrimination for both homozygotes and heterozygotes is the measurement of the amount of cholesterol oleate formed during the first 6 h of LDL uptake by cholesterol depleted nonconfluent fibroblasts.  Two genetic isolates, namely, NPC1 and NPC2, have been identified by complementation analysis and chromosomal localization of respective genes. More than 95% of patients belong to NPC1. The NPC1 gene contains a region common among genes involved in intracellular cholesterol homeostasis. Therapeutic strategies include the reduction of dietary cholesterol and apheresis techniques designed to reduce LDL cholesterol available to cells, reduction of the formation of LDL and increase in the synthesis of HDL to lower the cellular uptake of cholesterol and to enhance the egress of this lipid from the intracellular storage sites.  Treatment is largely symptomatic that provides rehabilitative measures and counsels the patients and family members.
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[Figure - 1], [Figure - 2]
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